Therapeutic compositions and methods of using serotonin modulating microbiome-based interventions to treat serotonin-related diseases or disorders

Abstract

The technology described herein is directed to compositions and methods for modulating serotonin in a subject. Described herein are compositions comprising viable or non-viable serotonin modulating bacteria, conditioned medium(s) of serotonin-modulating bacteria, cell pellet(s) of serotonin modulating bacteria, and/or metabolites and/or proteins derived from serotonin-modulating bacteria. Also described herein are methods of treating serotonin-related disease or disorders.

1 . A therapeutic composition for increasing serotonin level in a mammalian subject in need thereof, the composition comprising an amount of a live isolated serotonin-increasing bacterial species, dead isolated serotonin-increasing bacterial species, conditioned medium from an isolated, cultured serotonin-increasing bacterial species, cell pellet of an isolated serotonin-increasing bacterial species, a purified metabolite produced by an isolated serotonin-increasing bacterial species, a purified protein produced by an isolated serotonin-increasing bacterial species, or a combination thereof sufficient to increase serotonin level in the subject, and an excipient or carrier suitable for delivery to the gut. 
     
     
         2 . (canceled) 
     
     
         3 . The therapeutic composition of  claim 1 , wherein the isolated serotonin-increasing bacterial species comprises  Bifidobacterium adolescentis.    
     
     
         4 . The therapeutic composition of  claim 1 , wherein the serotonin increasing bacterial species comprises one or more species selected from  Enterococcus durans, Clostridium lavalense, Clostridium asparagiforme , and  Ruminococcus gnavus.    
     
     
         5 . (canceled) 
     
     
         6 . The therapeutic composition of  claim 1 , wherein the serotonin increasing bacterial species:
 (a) comprises a 16S sequence at least 95% identical to a 16S sequence selected from SEQ ID NOs: 1-4;   (b) comprises a 16S sequence at least 95% identical to a 16S sequence comprising SEQ ID NO: 12; or   (c) increases serotonin under conditions found in the mammalian gut.   
     
     
         7 . (canceled) 
     
     
         8 . The therapeutic composition of  claim 1 , wherein the mammalian subject is a human subject. 
     
     
         9 . The therapeutic composition of  claim 1 , wherein the serotonin-increasing bacterial species encodes and expresses:
 (a) a decarboxylase enzyme that catalyzes the production of tryptamine from tryptophan; and/or   (b) an enzyme that hydroxylates tryptamine to produce serotonin.   
     
     
         10 . The therapeutic composition of  claim 9 , wherein the decarboxylase enzyme:
 (a) is a tryptophan decarboxylase;   (b) belongs to the EC number 4.1.1.105;   (c) is at least 50% identical to an enzyme comprising an amino acid sequence selected from SEQ ID Nos: 115-119; or   (d) is a lysine decarboxylase family enzyme.   
     
     
         11 .- 13 . (canceled) 
     
     
         14 . The therapeutic composition of  claim 9 , wherein the enzyme that hydroxylates tryptamine is:
 (a) a tryptamine 5-hydroxylase;   (b) at least 50% identical to the enzyme of SEQ ID NO: 134; or   (c) an anaerobic hydroxylase.   
     
     
         15 .- 17 . (canceled) 
     
     
         18 . The therapeutic composition of  claim 1 , wherein the live isolated serotonin-increasing bacterial species, dead isolated serotonin-increasing bacterial species, conditioned medium from an isolated, cultured serotonin-increasing bacterial species or cell pellet of an isolated serotonin-increasing bacterial species comprises a bacterial species that encodes and expresses a decarboxylase enzyme that catalyzes the production of tryptamine from tryptophan. 
     
     
         19 . (canceled) 
     
     
         20 . The therapeutic composition of  claim 1 , wherein the serotonin-increasing bacterial species encodes and expresses:
 (a) an enzyme that converts tryptophan to 5-hydroxy-L-tryptophan (5-HTP); and/or   (b) an enzyme that converts 5-hydroxy-L-tryptophan to serotonin.   
     
     
         21 . The therapeutic composition of  claim 20 , wherein the enzyme that converts tryptophan to 5-hydroxy-L-tryptophan (5-HTP):
 (a) has an amino acid sequence at least 50% identical to a sequence selected from SEQ ID Nos: 120-126;   (b) belongs to the EC number 1.14.16.4;   (c) is a tryptophan hydroxylase; or   (d) is a phenylalanine hydroxylase.   
     
     
         22 .- 23 . (canceled) 
     
     
         24 . The therapeutic composition of  claim 20 , wherein the enzyme that converts 5-hydroxy-L-tryptophan to serotonin:
 (a) is an aromatic L-amino acid decarboxylase;   (b) belongs to the EC number 4.1.1.28; or   (c) is at least 50% identical to a sequence selected from SEQ ID NOs: 127-133.   
     
     
         25 .- 29 . (canceled) 
     
     
         30 . The therapeutic composition of  claim 1 , wherein the live isolated serotonin-increasing bacterial species, dead isolated serotonin-increasing bacterial species, conditioned medium from an isolated, cultured serotonin-increasing bacterial species or cell pellet of an isolated serotonin-increasing bacterial species comprises a bacterial species that encodes and expresses an enzyme that catalyzes the conversion of tryptophan to 5-hydroxy-L-tryptophan. 
     
     
         31 .- 33 . (canceled) 
     
     
         34 . The therapeutic composition of  claim 21 , wherein the phenylalanine hydroxylase comprises an amino acid sequence comprising one or more of phenylalanine at the position corresponding to W192, isoleucine or leucine at the position corresponding to F197, and cysteine at the position corresponding to E219 of the phenylalanine hydroxylase of  Cupriavidus taiwanensis  (SEQ ID NO: 227). 
     
     
         35 . A pharmaceutical composition comprising the therapeutic composition of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         36 . A method of increasing serotonin level in a mammalian subject in need thereof, the method comprising administering a composition of  claim 35  to the subject, whereby a serotonin level is increased. 
     
     
         37 . The method of  claim 36 , wherein the administering is to the gut of the subject. 
     
     
         38 . The method of  claim 36 , wherein the level of serotonin in the gut is increased. 
     
     
         39 . The method of  claim 36 , wherein the level of serotonin in circulation is increased. 
     
     
         40 . A method of treating a disease or disorder involving or characterized by low serotonin in a subject in need thereof, the method comprising administering a composition of  claim 35  to the subject, whereby the disease or disorder is treated. 
     
     
         41 .- 153 . (canceled)